Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial

Abstract

Importance: Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches.

Objective: To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity.

Design, setting, and participants: Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30).

Interventions: Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks.

Main outcomes and measures: The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight.

Results: Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants.

Conclusions and relevance: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.

Trial registration: ClinicalTrials.gov Identifier: NCT03611582.

Figure 1.. Participant Flow in the STEP 3 Trial of Semaglutide in Adults With Overweight or Obesity

^aParticipants could meet more than 1 exclusion or randomization criterion. ^bAdverse events leading to permanent discontinuation of trial product (participants may have discontinued due to ≥1 adverse event): (1) gastrointestinal disorders: constipation, n = 2 (semaglutide); diarrhea/explosive diarrhea, n = 2 (semaglutide); eructation/belching, n = 1 (semaglutide); flatulence/excessive gas, n = 1 (semaglutide); nausea/worsening nausea, n = 7 (semaglutide); retching/dry heaves, n = 1 (semaglutide); and vomiting/worsening vomiting/recurrent vomiting, n = 6 (semaglutide). (2) General disorders and administration site conditions/hepatobiliary disorders: biliary colic/gallbladder pain, n = 1 (semaglutide); biliary dyskinesia, n = 1 (semaglutide); and injection site hematoma, n = 1 (placebo). (3) Infections and infestations: diverticulitis, n = 1 (placebo). (4) Injury, poisoning, and procedural complications: concussion, n = 1 (semaglutide). (5) Investigations: amylase increased/elevated amylase, n = 1 (semaglutide); blood creatine phosphokinase increased/elevated creatine kinase, n = 1 (semaglutide); and lipase increased/elevated lipase, n = 1 (semaglutide). (6) Metabolism and nutrition disorders: loss of appetite, n = 1 (semaglutide). (7) Musculoskeletal and connective tissue disorders: right-sided flank pain, n = 1 (placebo). (8) Nervous system disorders: headache, n = 1 (semaglutide); and worsening of migraine, n = 1 (semaglutide). (9) Psychiatric disorders: anxiety/worsening anxiety, n = 3 (semaglutide), n = 1 (placebo). (10) Skin and subcutaneous tissue disorders: hair thinning, n = 1 (semaglutide); hair loss, n = 1 (placebo); burning under skin of the right leg, n = 1 (semaglutide); and generalized pruritic rash, n = 1 (placebo). ^cA total of 5.6% of participants were lost to follow-up. In the semaglutide group, 12 were lost to follow-up by week 38, and in the placebo group, 5 were lost to follow-up by week 25.

Figure 2.. Body Weight–Related Efficacy End Points

A, The observed mean percentage change in body weight over time for participants in the full analysis set for the in-trial period (from randomization to last contact with the trial site, regardless of treatment discontinuation or rescue intervention). Error bars represent 95% CIs of the mean. B, The observed proportions of participants attaining at least 5% (co–primary end point), 10%, 15%, and 20% reductions in baseline body weight by week 68 in the full analysis set. The proportions shown are cumulative, such that the 88.6% of semaglutide-treated participants who lost more than 5% of baseline body weight includes the 75.3% of participants who lost more than 10%, and so on. See eFigure 4 in Supplement 1 for corresponding on-treatment data (during treatment with the trial product [any dose of trial medication administered within the previous 2 weeks]).